Dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH.sub.2) is an amphibian heptapeptide that possesses potent opioid-like activity in humans (T. Sato et al., J. Pharmacol. Exp. Ther., 242, pp. 654-59 (1987)). Opioid peptides, such as dermorphin, bind with varying degrees of selectivity to peripherally- and centrally-located opioid receptors.
Three distinct categories of opioid receptors have been identified (designated .mu., .delta. and .kappa.) (W. Martin et al., J. Pharmacol. Exp. Ther., 197, p. 517 (1977); J. Lord et al., Nature, 257, p. 495 (1977)). Although there is no definitive correlation between the binding of particular opioid receptors and specific opioid effects, it appears that the .mu. receptors predominantly mediate analgesic effects, while the .delta. and .kappa.-receptors appear to mediate behavioral effects.
Lack of opioid receptor selectivity and access to the central nervous system has been linked to many dangerous side effects (such as physical dependence and respiratory depression). Conventional opiates (such as morphine, naloxone, levorphanol, enkephalin, endorphin and dynorphin) and analogs thereof are generally quite hydrophobic and are therefore, able to permeate lipid membranes, such as the blood-brain barrier. This permeability has been linked to CNS-related side effects, such as euphorea and addiction. In addition, conventional opiates typically are not highly selective for any particular type of opioid receptor. The side effects associated with the administration of opioid peptides and opioid peptide analogs have hindered their use as pharmacological agents.
In addition to undesired side effects, conventional opioid peptides tend to remain lodged in a patient's organs and fatty tissues. Such compounds must, therefore, be administered at high doses and are likely to cause toxic reactions associated with long term exposure to opiates.
Accordingly, there is a need for stable opioid peptide analogs that are potent analgesics. Such opioid peptide analogs should be highly .mu.-receptor selective, hydrophilic, peripherally-active and readily excreted from the body.